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Insights Into the Mode of Inhibition of Human Mitochondrial Monoamine Oxidase B from High-Resolution Crystal Structures

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Insights Into the Mode of Inhibition of Human Mitochondrial Monoamine Oxidase B from High-Resolution Crystal Structures Insights into the mode of inhibition of human mitochondrial monoamine oxidase B from high-resolution crystal structures Claudia Binda*, Min Li†, Frantisek Huba´ lek†, Nadia Restelli*, Dale E. Edmondson†‡, and Andrea Mattevi*‡ *Department of Genetics and Microbiology, University of Pavia, 27100 Pavia, Italy; and †Departments of Biochemistry and Chemistry, Emory University, Atlanta, GA 30322 Communicated by Judith P. Klinman, University of California, Berkeley, CA, June 23, 2003 (received for review April 11, 2003) Monoamine oxidase B (MAO-B) is an outer mitochondrial mem- We report here the structures of MAO-B in complex with brane-bound enzyme that catalyzes the oxidative deamination several reversible and irreversible inhibitors (Fig. 2) to elucidate of arylalkylamine neurotransmitters and has been a target for a their respective binding modes as well as to provide insights into number of clinically used drug inhibitors. The 1.7-Å structure of the mode of inhibition. Higher (1.7 Å) resolution data were the reversible isatin–MAO-B complex has been determined; it obtained that provide additional structural details on the ac- forms a basis for the interpretation of the enzyme’s structure tive site relevant to drug design and to the detailed catalytic when bound to either reversible or irreversible inhibitors. 1,4- mechanism. Diphenyl-2-butene is found to be a reversible MAO-B inhibitor, The structure of MAO-B in complex with isatin was deter- which occupies both the entrance and substrate cavity space in mined because this compound is found at higher levels in the enzyme. Comparison of these two structures identifies patients with neuropathological conditions and has been shown ␮ Ile-199 as a ‘‘gate’’ between the two cavities. Rotation of the to be a competitive MAO-B inhibitor with a Ki of 3 M (2). In side chain allows for either separation or fusion of the two the course of these studies, we have uncovered a competitive ϭ ␮ cavities. Inhibition of the enzyme with N-(2-aminoethyl)-p-chlo- MAO-B inhibitor (Ki 35 M) that is identified as 1,4-diphenyl- robenzamide results in the formation of a covalent N(5) flavin 2-butene, a contaminant of polystyrene products (3). adduct with the phenyl ring of the inhibitor occupying a position The structure of MAO-B after inhibition with N-(2- in the catalytic site overlapping that of isatin. Inhibition of aminoethyl)-p-chlorobenzamide (also known as Ro 16-6491) was MAO-B with the clinically used trans-2-phenylcyclopropylamine elucidated. This compound belongs to a class of highly specific results in the formation of a covalent C(4a) flavin adduct with an MAO-B inhibitors, which includes lazabemide. A previous study opened cyclopropyl ring and the phenyl ring in a parallel (4) suggested this inhibitor binds to a site on the enzyme other orientation to the flavin. The peptide bond between the flavin- than the flavin moiety. Tranylcypromine (trans-2-phenylcyclo- substituted Cys-397 and Tyr-398 is in a cis conformation, which propylamine) has been known for Ͼ40 years as a MAO inhibitor allows the proper orientation of the phenolic ring of Tyr-398 in and used clinically as an antidepressant. As with the lazabemide the active site. The flavin ring exists in a twisted nonplanar class of inhibitors, tranylcypromine has been thought to exert its conformation, which is observed in the oxidized form as well as inhibitory action as a mechanism-based inhibitor by covalent in both the N(5) and the C(4a) adducts. An immobile water binding of the MAO-B-catalyzed reaction product to an amino molecule is H-bonded to Lys-296 and to the N(5) of the flavin as acid side chain (5, 6). The structural data presented in this study observed in other flavin-dependent amine oxidases. The active show that, in contrast to previous conclusions, tranylcypromine site cavities are highly apolar; however, hydrophilic areas exist and N-(2-aminoethyl)-p-chlorobenzamide inhibit MAO-B by near the flavin and direct the amine moiety of the substrate for covalent binding to the flavin ring, however, at differing sites on binding and catalysis. Small conformational changes are ob- the isoalloxazine ring. served on comparison of the different inhibitor–enzyme com- plexes. Future MAO-B drug design will need to consider ‘‘in- Materials and Methods duced fit’’ contributions as an element in ligand–enzyme Expression, purification, absorption spectral studies, and cata- interactions. lytic assays of recombinant human liver MAO-B were performed as described (7). All chemicals used in this study were obtained he structure and function of monoamine oxidases A and B from commercial sources. T(MAO-A and -B) have been of interest to a wide variety of Orthorhombic MAO-B crystals were grown by the sitting-drop scientific disciplines because of the role of these enzymes in the vapor diffusion method at 4°C (1) using polystyrene micro- oxidation of arylalkylamine neurotransmitters such as dopamine bridges obtained from Hampton Research. The precipitant and serotonin. The proposed role of MAO-B in age-dependent solution consisted of 12% (wt͞vol) PEG 4000, 70 mM lithium neurodegenerative diseases has resulted in a renewed interest in sulfate, and 100 mM N-(2-acetamido)-2-iminodiacetic acid this enzyme as a target for the development of neuroprotective (ADA), pH 6.5. The protein solution contained 2 mg of MAO-B agents. MAO-B inhibitors are used clinically and others are in per ml, 8.5 mM Zwittergent 3–12, and 25 mM potassium development. MAO-A and -B have been extensively investigated phosphate buffer, pH 7.5. Crystals of enzyme–inhibitor com- and serve as the prototype for the flavin-dependent amine plexes were obtained by incubating the protein with 2 mM oxidases. inhibitor followed by gel filtration on Superdex 200. For all The recent description of the 3.0-Å structure of human recombinant MAO-B in its pargyline-inhibited form by our laboratories (1) revealed a two-domain architecture of the Abbreviation: MAO, monoamine oxidase. molecule and its mode of binding to the mitochondrial outer Data deposition: The atomic coordinates and the structure factors have been deposited in the Protein Data Bank, www.rcsb.org (PBD ID codes 1OJA, 1OJB, 1OJC, 1OJD, and 1OJ9). membrane through a C-terminal hydrophobic ␣-helix. These ‡To whom correspondence may be addressed at: (D.E.E.) Department of Biochemistry, studies show the substrate negotiates a protein loop in its entry Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322. E-mail: into the active site of the enzyme, which involves traversing an [email protected]; or (A.M.) Department of Genetics and Microbiology, ‘‘entrance cavity’’ before entering the ‘‘substrate cavity’’ (Fig. 1). University of Pavia, Via Abbiategrasso, 27100 Pavia, Italy. E-mail: [email protected]. 9750–9755 ͉ PNAS ͉ August 19, 2003 ͉ vol. 100 ͉ no. 17 www.pnas.org͞cgi͞doi͞10.1073͞pnas.1633804100 Downloaded by guest on September 30, 2021 atomic models were built with program O (12). Unbiased Ϫ Ϫ 2Fo Fc and Fo Fc maps were used to model the inhibitors which, in all cases, were well defined by the electron density maps (Fig. 3). The models exhibit good stereochemical pa- rameters with only three residues in each monomer (Lys-52, Ala 346, and Asp 419) in disallowed regions of the Ramachan- dran plot. The refinement statistics are listed in Table 1. Analysis of the final models were carried out with the pro- grams GRID (13) and VOIDOO (14). Pictures were produced by using LIGPLOT (15), BOBSCRIPT (16), MOLSCRIPT (17), and RASTER3D (18). Results and Discussion Structural Analysis of Reversible, Noncovalent Inhibitor–MAO-B Com- plexes. The tight, reversible binding of isatin (Fig. 2) to MAO-B has been known since its original identification (2). Isatin competitively binds to purified, recombinant MAO-B with a Ki of Ϸ3 ␮M. The tight binding of the inhibitor led to an improved crystal quality and diffraction data could be measured up to Fig. 1. Overall three-dimensional structure of human MAO-B monomeric 1.7-Å resolution (Table 1). A stereoview of this structure is unit in complex with 1,4-diphenyl-2-butene. The FAD-binding domain (resi- dues 4–79, 211–285, and 391–453) is in blue, the substrate-binding domain shown in Fig. 3. The electron density of the dioxoindole ring (residues 80–210, 286–390, and 454–488) is in red, and the C-terminal mem- shows its orientation in the substrate cavity to be perpendic- brane-binding region (residues 489–500) is in green. The FAD cofactor and the ular to the flavin ring with the oxo groups on the pyrrole ring inhibitor are shown as yellow and black ball-and-stick models, respectively. pointing toward the flavin. The 2-oxo group and the pyrrole The inhibitor binds in a cavity (shown as a cyan surface) that results from the NH are H-bonded to ordered water molecules present in the fusion of the entrance and substrate cavities (see text). active site, whereas the 3-oxo function is not involved in any H-bond. The balance of the binding interactions involve many van der Waals contacts between the isatin ring and amino acid BIOCHEMISTRY inhibitors except tranylcypromine, 2 mM inhibitor was added to residues in the solvent-inaccessible, hydrophobic substrate the crystallization drop. Triclinic crystals were grown as de- cavity. scribed (1). X-ray diffraction data were collected at 100 K at the An unanticipated noncovalent inhibitor of MAO-B was ser- Swiss Light Source in Villigen and at the beam-line ID14-EH4 endipitously discovered when we attempted to determine the of the European Synchrotron Radiation Facility in Grenoble, structure of the enzyme in the presence of d-amphetamine.
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